Novel Association Between Immune-Mediated Susceptibility Loci and Persistent Autoantibody Positivity in Type 1 Diabetes
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Novel Association Between Immune-Mediated Susceptibility Loci and Persistent Autoantibody Positivity in Type 1 Diabetes. / Brorsson, Caroline A; Onengut, Suna; Chen, Wei-Min; Wenzlau, Janet; Yu, Liping; Baker, Peter; Williams, Alistair J K; Bingley, Polly J; Hutton, John C; Eisenbarth, George S; Concannon, Patrick; Rich, Stephen S; Pociot, Flemming; Type 1 Diabetes Genetics Consortium.
I: Diabetes, Bind 64, Nr. 8, 08.2015, s. 3017-27.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Novel Association Between Immune-Mediated Susceptibility Loci and Persistent Autoantibody Positivity in Type 1 Diabetes
AU - Brorsson, Caroline A
AU - Onengut, Suna
AU - Chen, Wei-Min
AU - Wenzlau, Janet
AU - Yu, Liping
AU - Baker, Peter
AU - Williams, Alistair J K
AU - Bingley, Polly J
AU - Hutton, John C
AU - Eisenbarth, George S
AU - Concannon, Patrick
AU - Rich, Stephen S
AU - Pociot, Flemming
AU - Type 1 Diabetes Genetics Consortium
N1 - © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
PY - 2015/8
Y1 - 2015/8
N2 - Islet autoantibodies detected at disease onset in patients with type 1 diabetes are signs of an autoimmune destruction of the insulin-producing β-cells. To further investigate the genetic determinants of autoantibody positivity, we performed dense immune-focused genotyping on the Immunochip array and tested for association with seven disease-specific autoantibodies in a large cross-sectional cohort of 6,160 type 1 diabetes-affected siblings. The genetic association with positivity for GAD autoantibodies (GADAs), IA2 antigen (IA-2A), zinc transporter 8, thyroid peroxidase, gastric parietal cells (PCAs), tissue transglutaminase, and 21-hydroxylase was tested using a linear mixed-model regression approach to simultaneously control for population structure and family relatedness. Four loci were associated with autoantibody positivity at genome-wide significance. Positivity for GADA was associated with 3q28/LPP, for IA-2A with 1q23/FCRL3 and 11q13/RELA, and for PCAs with 2q24/IFIH1. The 3q28 locus showed association after only 3 years duration and might therefore be a marker of persistent GADA positivity. The 1q23, 11q13, and 2q24 loci were associated with autoantibodies close to diabetes onset and constitute candidates for early screening. Major susceptibility loci for islet autoantibodies are separate from type 1 diabetes risk, which may have consequences for intervention strategies to reduce autoimmunity.
AB - Islet autoantibodies detected at disease onset in patients with type 1 diabetes are signs of an autoimmune destruction of the insulin-producing β-cells. To further investigate the genetic determinants of autoantibody positivity, we performed dense immune-focused genotyping on the Immunochip array and tested for association with seven disease-specific autoantibodies in a large cross-sectional cohort of 6,160 type 1 diabetes-affected siblings. The genetic association with positivity for GAD autoantibodies (GADAs), IA2 antigen (IA-2A), zinc transporter 8, thyroid peroxidase, gastric parietal cells (PCAs), tissue transglutaminase, and 21-hydroxylase was tested using a linear mixed-model regression approach to simultaneously control for population structure and family relatedness. Four loci were associated with autoantibody positivity at genome-wide significance. Positivity for GADA was associated with 3q28/LPP, for IA-2A with 1q23/FCRL3 and 11q13/RELA, and for PCAs with 2q24/IFIH1. The 3q28 locus showed association after only 3 years duration and might therefore be a marker of persistent GADA positivity. The 1q23, 11q13, and 2q24 loci were associated with autoantibodies close to diabetes onset and constitute candidates for early screening. Major susceptibility loci for islet autoantibodies are separate from type 1 diabetes risk, which may have consequences for intervention strategies to reduce autoimmunity.
KW - Autoantibodies
KW - Autoimmunity
KW - Cross-Sectional Studies
KW - Diabetes Mellitus, Type 1
KW - Genetic Association Studies
KW - Genetic Loci
KW - Genetic Predisposition to Disease
KW - Genotype
KW - Humans
U2 - 10.2337/db14-1730
DO - 10.2337/db14-1730
M3 - Journal article
C2 - 25829454
VL - 64
SP - 3017
EP - 3027
JO - Diabetes
JF - Diabetes
SN - 0012-1797
IS - 8
ER -
ID: 162216361